Pd-catalyzed α-arylation of thioamides

Article abstract of DOI:10.1016/j.tetlet.2013.03.114

Thioamides are unique and versatile synthetic building blocks with S, N, and α-C three adjacent nucleophile centers, however, they are rarely used as carbon nucleophiles for transition-metal-catalyzed C-C coupling reactions. This Letter describes the first Pd-catalyzed α-arylation of thioamides and demonstrated the feasibility of the application of thioamides in coupling chemistry. By the coupling process, a variety of α-arylated thioamides were prepared in moderate to good yields under mild reaction conditions, which provides an alternative way to access functionalized thioamides as well as a new synthetic transformation for thioamides. High chemoselectivity for thioamide over amide was observed in the reaction.

Full text of DOI:10.1016/j.tetlet.2013.03.114

Tetrahedron Letters 54 (2013) 3060–3062
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd-catalyzed a-arylation of thioamides
⇑
Hailei Yu, Xuliang Liu, Lei Ding, Qin Yang, Bin Rong, Ang Gao, Baoguo Zhao , Haifeng Yang
Key Laboratory of Resource Chemistry of Ministry of Education, Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University, Shanghai 200234, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Thioamides are unique and versatile synthetic building blocks with S, N, and a-C three adjacent nucleo-
Received 23 January 2013
Revised 18 March 2013
Accepted 25 March 2013
Available online 6 April 2013
phile centers, however, they are rarely used as carbon nucleophiles for transition-metal-catalyzed C–C
coupling reactions. This Letter describes the first Pd-catalyzed -arylation of thioamides and demon-
strated the feasibility of the application of thioamides in coupling chemistry. By the coupling process,
a variety of -arylated thioamides were prepared in moderate to good yields under mild reaction condi-
a
a
tions, which provides an alternative way to access functionalized thioamides as well as a new synthetic
transformation for thioamides. High chemoselectivity for thioamide over amide was observed in the
reaction.
Keywords:
a-Arylation
Palladium
Thioamide
Coupling
Catalysis
Ó 2013 Elsevier Ltd. All rights reserved.
Thioamides are important synthetic building blocks with sulfur,
nitrogen, and a-carbon three adjacent nucleophilic centers, which
the palladium catalyst was necessary for the transformation (Table
1, entry 1 vs 2). [Pd(C3H5)Cl]2 was the most efficient catalyst. The
sulfur atom of thioamide did not poison the palladium catalyst at
all. Phosphine ligand also played an important role in the reaction
(Table 1, entry 8 vs entries 7 and 9–11) and PPh3 was the choice of
have been extensively used to synthesize a wide variety of signif-
icant molecules, especially to construct various heterocyclic com-
pounds, by reaction with many kinds of electrophiles.1,2 Although
thioamides have displayed wide applications in organic synthe-
sis,1,2 they are rarely used as carbon nucleophiles for transition-
metal-catalyzed C–C coupling reactions.3–5 Pd- and Ni-catalyzed
the ligand for the
Substrate scope was then investigated by using [Pd(C3H5)Cl]2-
PPh3 as catalyst (Table 2). Various thioamides were smoothly
a-arylation of thioamides (Table 1, entry 7).
a-
a
-arylation of carbonyl compounds has emerged as one of the
arylated to give the corresponding coupling products in moderate
most useful synthetic tools for sp2–sp3 C–C bond formation
to good yields under the optimized conditions.14 Aryl bromides
(Scheme 1).5,6 However, the corresponding Pd- and Ni-catalyzed
were as active as iodobenzene in the
a-arylation of thioamides.
a
-arylation of thioamides has not been explored so far (Scheme
1). As compared to structurally related amides, thioamides have
more acidic
-protons7 and higher coordination abilities to transi-
However, aryl chloride such as chlorobenzene (2e) was totally inef-
fective for the reaction (Table 2, entry 10). Functional groups such
as C–C double bond and OTBS were well tolerated by the reaction
(Table 2, entries 13 and 14). High selectivity in monoarylation was
observed in the reaction and no diarylated product was isolated in
all cases. Disubstituted thioamides such as N,N-dimethyl-2-ethylh-
a
tion metal centers, which might lead to specific reactivities and
unique selectivities for thioamides in transition-metal-catalyzed
C–C coupling reactions. Moreover, thioamides can be facilely
transformed into many other vital functional groups including
amines,4a,8 aldehydes,4c,9 amides,10 acids,11 thioesters,12 and
b-ketoesters.4c,13 Considering the synthetic importance, unique
properties, and facile functionalization of thioamides, it should
exanethioamide are not effective for the
a-arylation under the
be highly desirable to explore Pd-catalyzed a-arylation of thioam-
ides. Herein, we wish to report our preliminary studies on this
project.
Initial investigation was carried out with N,N-dimethyl-3-phe-
nylpropanethioamide (1a) and iodobenzene (2a) by using
Pd(PPh3)4 as catalyst (Table 1, entry 2). The a-arylation of thioam-
O
O
R1
R1
R1
Cat: [Pd] or [Ni]
base
R3
Ar
X
R3
+
(ref. 5-6)
R2
R2
Ar
S
S
R1
R2
Cat: [Pd]
base
ide 1a occurred in 86% conversion. Further screening showed that
NR3
(this work)
+
NR3
Ar
X
2
2
R2
Ar
⇑
Corresponding author.
E-mail address: zhaobg2006@shnu.edu.cn (B. Zhao).
Scheme 1.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.114

H. Yu et al. / Tetrahedron Letters 54 (2013) 3060–3062
3061
Table 1
Table 2 (continued)
Screening of reaction conditions for Pd-catalyzed
a
-arylation of thioamidesa
Entry Thioamide (1)
ArX (2)
Yieldb (%)
S
I
Br
S
[Pd] (5 mol %)
N
NaOt-Bu (1.2 equiv)
N
+
toluene,100 oC, 6 h
2f
11
1f
1f
66
1a
3aa
2a
Conv.b (%)
2f
Entry
[Pd]
Ligand
Br
1
2
3
4
5
6
7
8
9
None
PPh3
—
PPh3
PPh3
PPh3
PPh3
PPh3
—
0
86
68
94
80
83
96
0
Pd(PPh3)4
Pd2(dba)3
Pd(OAc)2
PdCl2
Pd(C6H5CN)2Cl2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
2g
12
13
51
55
2g
S
7
N
1g
2a
2b
PCy3
P(OPh)3
dppb
70
40
74
1g
10
11
OTBS
S
a
n-C7H15
N
All the reactions were carried out with N,N-dimethyl-3-phenylpropanethioa-
1h
14
67
mide (1a) (0.40 mmol), iodobenzene (2a) (1.0 mmol), NaOt-Bu (0.48 mmol), Pd
(0.020 mmol), and ligand (0.050 mmol for monodentate ligand and 0.025 mmol for
dppb) in toluene (2 mL) at 100 °C for 6 h unless otherwise stated.
1h
b
The conversion was based on thioamide 1a and determined by 1H NMR analysis
a
All the reactions were carried out with thioamide 1 (0.40 mmol), haloarene (2)
of the crude reaction mixture.
(0.60 mmol), NaOt-Bu (0.48 mmol), [Pd(C3H5)Cl]2 (0.010 mmol), and PPh3
(0.050 mmol) in toluene (2 mL) at 100 °C for 6 h unless otherwise stated. For entries
1 and 2, iodobenzene (2a) (1.0 mmol) was used.
b
The isolated yield was based on thioamide 1.
Table 2
Pd-catalyzed
a
-arylation of thioamidesa
reaction conditions possibly due to the steric hindrance of the
substrate.
[Pd(C3H5)Cl]2 (2.5 mol %)
PPh3 (12.5 mol %
S
S
R1
R3
R1
R3
Competition experiment between thioamide 1a and the struc-
N
N
+
Ar
X
NaOt-Bu (1.2 equiv)
Ar R2
R2
turally related amide 4 was carried out for the Pd-catalyzed
lation (Scheme 2). The arylation highly selectively occurred on
thioamide 1a, giving
-phenyl thioamide 3a in 41% yield.15
The high chemoselectivity for thioamide over amide observed in
the experiment is probably due to the higher -H acidity and/or
a-ary-
toluene,100 oC, 6 h
1
2
3
a
Entry Thioamide (1)
ArX (2)
Yieldb (%)
S
I
a
the better coordination capability of thioamide 1a than amide 4.
While a precise reaction mechanism awaits further studies, a
plausible catalytic cycle is proposed in Scheme 3. Active catalyst
Pd(0) complex 6 inserts into the C–X bond of haloarene 2 to form
ArPd(II)X species 7. Compound 7 reacts with thioamide 1 under ba-
sic conditions to give a mixture of S–Pd complex 8a and C–Pd com-
plex 8b, which are likely in equilibrium under the reaction
conditions. C–Pd complex 8b undergoes reductive elimination to
NR2
1
60
60
1a: R = Me
2a
2
3
1b: R = Et
2a
S
Br
N
1c
52
63
MeO
form
a-arylation product 3 and regenerate the Pd(0) catalyst 6,
1c
completing the catalytic cycle.
2b
In summary, this is the first report on Pd-catalyzed a-arylation
of thioamides,16–19 which has demonstrated the feasibility of the
S
N
application of thioamides in coupling chemistry. Various
a-aryl
1d
N
4
2a
thioamides were prepared in moderate to good yields by the
Pd-catalyzed
a
-arylation. The current coupling process provides
1d
S
S
n-C6H13
S
S
1e
1f
5
6
2a
62
64
Ph
3a
N
Ph
1a
N
1e
Ph
[Pd(C3H5)Cl]2 (2.5 mol %)
PPh3 (12.5 mol %)
C6H5I (0.60 mmol)
NaOt-Bu (0.48 mmol)
toluene,100 oC, 6 h
X
(0.40 mmol)
(41% yield)
n-C8H17
+
N
+
R
O
O
2a: X = I, R = H
Ph
N
Ph
N
7
8
9
1f
1f
1f
1f
2b: X = Br, R = 4-Me 71
2c: X = Br, R = 4-t-Bu 60
2d: X = Br, R = 3-Me 52
Ph
(0%)
4 (0.40 mmol)
5
10
2e: X = Cl, R = H
0
Scheme 2. Competition experiment between thioamide 1a and the related amide 4
for Pd-catalyzed -arylation.
a

3062
H. Yu et al. / Tetrahedron Letters 54 (2013) 3060–3062
Chem., Int. Ed. 2009, 48, 5026; (b) Iwata, M.; Yazaki, R.; Suzuki, Y.; Kumagai, N.;
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LnPd(0)
R
Ar
2
X
N
6
Ar
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3
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S
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Ln
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Ar Pd X
6. For selected references on transition-metal-catalyzed
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Ar PdLn
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Scheme 3. Proposed reaction mechanism for Pd-catalyzed
thioamides.
a
-arylation of
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an alternative synthetic method of functionalized thioamides
which are present in many chemically and biologically important
molecules.1d,20–23 Moreover, this work presents a new synthetic
transformation of thioamides, which might expand the applica-
tions of thioamides in organic synthesis.1,2 Further studies on
detailed reaction mechanism, substrate scope, catalyst develop-
ment as well as asymmetric processes are currently underway.
14. Some unidentified by-products were formed in the Pd(0)-catalyzed a-arylation
of N,N-dimethyl-3-phenylpropanethioamide (1a) with iodobenzene (2a) (Table
2, entry 1) as judged by 1H NMR spectroscopy of the crude reaction mixture.
15. The corresponding
a-arylation product of amide (5) was not isolated in the
competition experiment.
16. For selected references on synthesis of thiamides by using Lawesson reagent or
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We are grateful for the generous financial support from the Pro-
gram of Professor of Special Appointment (Eastern Scholar) at the
Shanghai Institutions of Higher Learning, the National Natural Sci-
ence Foundation of China (21272158), the Natural Science Founda-
tion of Shanghai City of China (12ZR1421900), the Innovation
Program of Shanghai Municipal Education Commission
(13YZ055), and the Pujiang Talents Programme (12PJ1406900).
Supplementary data
Supplementary data (the procedure of the Pd-catalyzed
a
-aryla-
tion of thioamides and the characterization of the
a-arylated thio-
amides 3 along with the 1H and 13C NMR spectra of 3) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2013.03.114.
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